It is well-known that metals such as molybdenum, vanadium, as well as gold and platinum, in particular, can be used in the therapy of acute and chronic diseases such as rheumatism, cancer or autoimmune diseases. Frequently, the metals being used are contacted in the form of complex compounds with the organism to be treated—in many cases via oral ingestion.
The complex compounds comprising the metals are difficult to produce with the required pharmaceutical purity. Numerous production methods which have been described either fail to generate the compounds with sufficient pharmaceutical purity or result in numerous byproducts giving rise to undesirable side effects in the organism. In particular, the preparation of pharmaceutically interesting cis- and trans-oxoplatinum compounds with the required purity or absence of byproducts is not possible with known methods (SU 1137698 A1, SU 1021116 A1). SU 1 137 698 A1 discloses preparation methods for cis-diaminodichlorodihydroxoplatinum(IV). The preparation methods disclosed therein achieve a purity of the final product of 99 to 99.6%.
Furthermore, various acyl derivatives of cis-platinum compounds have been disclosed in the prior art (Kelland et al., Cancer Research, 1992). According to the teaching of Kelland et al., it is the substituents on the nitrogen residue, rather than the acyl residues, that are essential to the effect of these compounds on ovarian cancer cell lines. In the opinion of the authors, there is a close relationship between the substituents on the nitrogen residue and the cytotoxic activity of the compounds. The cytotoxic activity of the cis-platinum compounds increases with increasing amounts of carbon atoms of the substituents on the nitrogen residue. That is, according to the explanations given by Kelland et al., a person skilled in the art would have had no motivation of replacing acyl residues by other moieties, e.g. alkyl residues, because the attention of a person skilled in the art has been drawn to the substituents on the nitrogen residue by Kelland et al. According to Kelland et al., it would make sense to a person skilled in the art to introduce substituents having a preferably large number of carbon atoms as substituent on the nitrogen residue into the respective cis-platinum compounds. According to Kelland et al., ring compounds are particularly advantageous, and a person skilled in the art would therefore be motivated to incorporate other, especially very large, ring compounds in the cis-platinum compounds by means of amine ligand substitution.
The object of the invention was therefore to provide a method allowing easy, reliable and effective provision of cis- or trans-oxoplatinum compounds.
The invention accomplishes the above object by means of a method for the preparation of cis- or trans-diammoniumdichlorodihydroxoplatinum(IV) or diammoniumdichloro-trans-dihydroxoplatinum(IV) and derivatives thereof, wherein cis- or trans-diammoniumdichloroplatinum(II) is reacted with a solution comprising >30% peroxide at temperatures below 30° C., and the product thus obtained is dissolved in a mineral acid and subsequently precipitated with an alkaline solution.
Surprisingly, the combination of features of a solution comprising >30% peroxide and relatively low temperatures, i.e., temperatures below 30° C., allows easy and reliable production of oxo-cis-platinum and oxo-trans-platinum compounds in such a way that small amounts of undesirable by-products are obtained. The method according to the invention utilizes cis- or trans-diammoniumdichloroplatinum(II) compounds as starting compounds, which are converted into the corresponding cis- or trans-form of diammoniumdichloro-trans-dihydroxoplatinum(IV). Advantageously, the solution comprising peroxide is added to the starting compound over a prolonged period of time, preferably in a continuous fashion. The solutions comprising peroxide can be solutions which liberate peroxide during the reaction or behave in a functionally analogous manner due to their specific structure, as is the case with e.g. hydrogen peroxide solutions or perchloroacetic acid solutions.